Inhibition of liver trans-sulphuration pathway by propargylglycine mimics gene expression changes found in the mammary gland of weaned lactating rats: role of glutathione

In the lactating mammary gland, weaning produces mitochondrial cytochrome c release and nuclear DNA fragmentation, as determined by gel electrophoresis. This is followed by a significant decrease in lactation. Weaning for 2 h produces an early induction of the tumour suppressor/transcription factor p53, whereas the oncoprotein c-Jun and c-Jun N-terminal kinase are elevated after 24 h of weaning when compared with controls. The expression of p21cip1 and p27kip1, cyclin-dependent kinase inhibitors, was significantly higher in weaned rats when compared with control lactating rats. All the changes mentioned above also happen in the lactating mammary gland when propargylglycine, an inhibitor of the liver trans-sulphuration pathway, is administered. This effect is partially reversed by N-acetylcysteine administration. The administration of buthionine sulphoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, to lactating rats produces a decrease in GSH levels and changes in protein concentrations and gene transcripts similar to those in rats with impaired trans-sulphuration pathway. These data suggest that the inter-tissue flux of GSH is an important mechanism of l-cysteine delivery to the lactating mammary gland and emphasize the importance of this physiological event in maintaining the gene expression required to sustain lactation.

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Role of GSH in the modulation of NOS-2 expression in the weaned mammary gland

Biochemical Society Transactions ◽

10.1042/bst0331397 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1397-1398

Author(s):

R. Zaragozá ◽

E.R. García-Trevijano ◽

V.J. Miralles ◽

M. Mata ◽

C. García ◽

...

Keyword(s):

Gene Expression ◽

Mammary Gland ◽

Mrna Expression ◽

Expression Patterns ◽

Microarray Experiment ◽

Oligonucleotide Microarray ◽

Lactating Mammary Gland ◽

Buthionine Sulphoximine

GSH delivery to the lactating mammary gland is essential for the maintenance of lactation as its decrease leads to apoptosis and involution of the mammary gland. In fact, it has already been demonstrated that some of the changes in gene expression found in the lactating mammary gland after forced weaning are reproduced in rats treated with buthionine sulphoximine to deplete GSH levels. An oligonucleotide microarray experiment would give us a better knowledge of the mRNA expression patterns during lactation and after weaning and the possible functions of GSH in the modulation of these events.

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Studies of the regulation of the mouse carboxyl ester lipase gene in mammary gland

Biochemical Journal ◽

10.1042/bj3360577 ◽

1998 ◽

Vol 336 (3) ◽

pp. 577-585 ◽

Cited By ~ 17

Author(s):

Marie KANNIUS-JANSON ◽

Ulf LIDBERG ◽

Kåre HULTÉN ◽

Amel GRITLI-LINDE ◽

Gunnar BJURSELL ◽

...

Keyword(s):

Gene Expression ◽

Mammary Gland ◽

Gene Promoter ◽

Positive Element ◽

Lipase Gene ◽

Lactating Mammary Gland ◽

Lactogenic Hormones ◽

Nuclear Factor 1 ◽

Promoter Studies ◽

Mammary Gland Differentiation

The lactating mammary gland and pancreas of mouse constitute the main tissues for synthesis and secretion of a bile-salt-stimulated lipase called carboxyl ester lipase (CEL). In this paper we have analysed the endogenous CEL gene expression in mammary gland. It is shown that the gene is expressed at day 14 of pregnancy, which is synchronous with that of the whey acidic protein (WAP) gene. Even though the CEL and WAP genes are induced at the same time during mammary gland differentiation, their regulation is different with respect to dependence on lactogenic hormones. The high induction of the WAP gene expression due to the activation of signal transducer and activator of transcription (STAT)5 by prolactin has not been observed for the CEL gene, even though it has been demonstrated that both STAT5 isoforms interact with one of the γ-interferon activation sequence sites in the promoter of the CEL gene. Hence we have demonstrated that the prolactin/STAT5 signal is not involved in a general and significant activation of ‘milk genes ’. Instead of a direct effect of the lactogenic hormones, the up-regulation of the CEL gene is correlated with an increase in the number of differentiated epithelial cells. Furthermore, promoter studies using the mammary-gland-derived cell line, HC11, show that a major positive element in the CEL gene promoter interacts with a member(s) of the CCAAT-binding transcription factor/nuclear factor 1 family, binding to a palindromic site. Binding of this factor(s) is important for the tissue-specific activation of the CEL gene in the mammary gland, because no activation by this factor(s) was seen in cells of pancreatic origin.

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Goat’s αS1-casein polymorphism affects gene expression profile of lactating mammary gland

animal ◽

10.1017/s1751731108001584 ◽

2008 ◽

Vol 2 (4) ◽

pp. 566-573 ◽

Cited By ~ 21

Author(s):

S. Ollier ◽

S. Chauvet ◽

P. Martin ◽

Y. Chilliard ◽

C. Leroux

Keyword(s):

Gene Expression ◽

Mammary Gland ◽

Gene Expression Profile ◽

Expression Profile ◽

Lactating Mammary Gland

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EFFECT OF LOCALLY IMPLANTED OESTROGEN ON THE RESPONSE OF THE RAT'S LACTATING MAMMARY GLAND TO OXYTOCIN

Acta Endocrinologica ◽

10.1530/acta.0.0730700 ◽

1973 ◽

Vol 73 (4) ◽

pp. 700-712 ◽

Cited By ~ 1

Author(s):

J. D. Bruce ◽

X. Cofre ◽

V. D. Ramirez

Keyword(s):

Mammary Gland ◽

Mammary Glands ◽

Myoepithelial Cells ◽

Recording System ◽

Saline Infusion ◽

High Dose ◽

Low Doses ◽

Milk Ejection ◽

Lactating Mammary Gland ◽

Small Rise

ABSTRACT On the day following delivery (day 1 of lactation) one abdominal mammary gland was implanted with oestrogen and the contralateral gland received an empty needle. At 2, 5 or 10 days of lactation the rats were anaesthetized with pentobarbital and the nipples of both abdominal glands were cannulated and their pressures recorded by means of transducers coupled to an amplifier and recording system. The normal mammary glands of 5-day lactating rats responded to very low doses of oxytocin (Syntocinon®, Sandoz) (5× 10−8 mU) with a rhythmic elevation in pressure. However, saline infusion also evoked a small rise in intra-mammary pressure. Earlier (2 days) and later (10 days) in lactation the responses were smaller. Oestrogen decreases significantly the milk ejection response to oxytocin, and the effect was maximal at day 10 of lactation. Histological observations confirmed the diminished reaction of the gland to oxytocin, since the milk was retained in the alveoli of rats bearing a mammary-oestrogen implant. A paradoxical rise in pressure was detected in normal as well as in oestrogen-implanted glands when the lowest dose of oxytocin was injected in lactating rats which had previously received a high dose of oxytocin (50 mU or 500 mU). These results reinforce the hypothesis that oestrogen alters the milk ejection response to oxytocin and that the mechanism is probably related to changes in the contractility of the myoepithelial cells.

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ÜBER DIE WIRKUNG PHARMAKOLOGISCHER OXYTOCINDOSEN AUF DIE MILCHDRÜSE

Acta Endocrinologica ◽

10.1530/acta.0.xxxiv0543 ◽

1960 ◽

Vol XXXIV (IV) ◽

pp. 543-557 ◽

Cited By ~ 12

Author(s):

B. Berde ◽

A. Cerletti

Keyword(s):

Mammary Gland ◽

Intravenous Administration ◽

Intravenous Infusion ◽

Intranasal Administration ◽

Intramuscular Injection ◽

Different Types ◽

Lactating Mammary Gland ◽

Synthetic Oxytocin

ABSTRACT A study was made of the influence of pharmacological amounts of synthetic oxytocin (»Syntocinon«) on the lactating mammary gland of the rabbit. The drug was given by intravenous infusion, by intramuscular injection and by intranasal administration. Two different types of reaction were noted: a tonic reaction, i. e. a lasting increase in pressure in the mammary gland without significant fluctuations, or a rhythmic reaction, i. e. a series of increases in pressure at more or less regular intervals. In order to elicit reactions approximately identical in intensity and character with those produced by intravenous infusion, it was necessary to give approximately 1.5 to 8.0 times as much by intramuscular injection and approximately 10 to 100 times as much by intranasal administration. Intravenous administration of adrenaline transiently suppressed a long-lasting reaction to oxytocin.

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Faculty Opinions recommendation of In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8291967.8722067 ◽

2011 ◽

Author(s):

Paul Terry ◽

Jiangang Chen

Keyword(s):

Gene Expression ◽

Experimental Study ◽

Mammary Gland ◽

Gene Expression Profile ◽

Expression Profile ◽

In Utero ◽

In Utero Exposure ◽

Butyl Benzyl Phthalate

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Multihormonal Regulation of Casein Gene Expression at the Transcriptional and Posttranscriptional Levels in the Mammary Gland

Proceedings of the 1979 Laurentian Hormone Conference ◽

10.1016/b978-0-12-571136-4.50011-5 ◽

1980 ◽

pp. 157-193

Author(s):

JEFFREY M. ROSEN ◽

ROBERT J. MATUSIK ◽

DONALD A. RICHARDS ◽

PRABHAKAR GUPTA ◽

JOHN R. RODGERS

Keyword(s):

Gene Expression ◽

Mammary Gland ◽

Casein Gene

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Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Journal of Translational Medicine ◽

10.1186/s12967-021-02764-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lydia Ntari ◽

Christoforos Nikolaou ◽

Ksanthi Kranidioti ◽

Dimitra Papadopoulou ◽

Eleni Christodoulou-Vafeiadou ◽

...

Keyword(s):

Gene Expression ◽

Therapeutic Effect ◽

Expression Analysis ◽

Mode Of Action ◽

Gene Expression Analysis ◽

Kinase Inhibitors ◽

High Dose ◽

Dependent Manner ◽

Combination Therapies ◽

Number Of Patients

Abstract Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

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